Visceral pain is currently the leading cause for patient visits in the U.S and is the main debilitating aspect inirritable bowel syndrome (IBS). The incidence of IBS is higher among individuals who experienced adverseevents during childhood, including verbal, physical and sexual abuse, as well as disease of later affectedorgans. The focus of the parent K01 proposal was a novel mouse model of neonatal colon irritation (NCI) thatreproduced the principal characteristic of IBS - colon hypersensitivity in the absence of histopathology. Themain hypothesis was that early insult in the viscerosensory system produces a long-lasting alteration innociceptive processing at the level of the colon, peripheral nerve and DRG. The current proposal aims tobroaden the focus of the original K01 award, by adding a model of neonatal stress (neonatal maternalseparation [NMS]) to the ongoing studies of NCI in an attempt to gain a more complete understanding of thevulnerabilities of the developing viscerosensory system and the long-lasting deleterious effects that can resultfrom perturbations during the neonatal critical period. The experiments in this application are outlined in twospecific aims and are designed to functionally test the hypothesis that NMS produces lifelong visceralhypersensitivity in mice through heightened excitability of peripheral sensory neurons due to changes inexpression of specific membrane receptors, which exacerbate the response to experimental colitis. SA1: Totest the hypothesis that NMS in mice produces long-lasting colon hypersensitivity and increasedexcitability/receptor changes in peripheral nerves innervating the distal colon. To test this hypothesis, a) thevisceromotor response (VMR) to colorectal distension will be evaluated in adult NMS mice and b) single cellRT-PCR and calcium imaging will be performed on colon DRG neurons to determine changes in expression,function and interactions between TRPV1 and TRPA1, two channels proposed to regulate visceral sensitivity.SA2: To test the hypothesis that NMS enhances susceptibility to experimental colitis and exacerbatesinflammation-induced changes in the distal colon and associated peripheral sensory neurons. To test thishypothesis, trinitrobenzene sulfonic acid (TNBS) will be administered to induce colitis and a) the extent ofinflammation will be determined by assessing increases in myeloperoxidase (MPO) activity and growth factorproduction, and b) VMR, single cell RT-PCR and calcium imaging will be repeated to determine how colitisaffects the already altered nociceptive processing in the NMS mice. The addition of the NMS model to ongoingstudies of NCI allows for comparisons to be made between two different models of neonatal insult with thesame behavioral outcome, heightened visceral sensitivity. Discoveries made using these models will allow forthe identification of common and/or divergent pathways that underlie visceral hypersensitivity, which couldserve as potential therapeutic targets for treatment of IBS and other functional bowel disorders.

Public Health Relevance

The focus of my research is on how adverse events during neonatal development can permanently alter pain processing in adulthood. As neonatal care improves, early gestational-age infant survival rates are increasing. However, these premature infants can spend weeks or months in the neonatal care unit where they are subjected to adverse conditions, both in terms of stress from maternal separation and from the multiple painful interventions required on a daily basis. The experiments included in this proposal will address neonatal stress- related outcomes in visceral pain processing, in terms of colon sensitivity, the expression of pain-related molecules on neurons innervating the colon and susceptibility to future colon insult (inflammation).

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Small Research Grants (R03)
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Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
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Podskalny, Judith M,
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University of Kansas
Anatomy/Cell Biology
Schools of Medicine
Kansas City
United States
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Fuentes, Isabella M; Walker, Natalie K; Pierce, Angela N et al. (2016) Neonatal maternal separation increases susceptibility to experimental colitis and acute stress exposure in male mice. IBRO Rep 1:10-18
Pierce, Angela N; Zhang, Zhen; Fuentes, Isabella M et al. (2015) Neonatal vaginal irritation results in long-term visceral and somatic hypersensitivity and increased hypothalamic-pituitary-adrenal axis output in female mice. Pain 156:2021-31
Fuentes, Isabella M; Pierce, Angela N; O'Neil, Pierce T et al. (2015) Assessment of Perigenital Sensitivity and Prostatic Mast Cell Activation in a Mouse Model of Neonatal Maternal Separation. J Vis Exp :e53181
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